Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation

Morrison, Nigel A., Stephens, Alexandre A., Osato, Motomi, Polly, Patsie, Tan, Timothy C., Yamashita, Namiko, Doecke, James D., Pasco, Julie, Fozzard, Nicolette, Jones, Graeme, Ralston, Stuart H., Sambrook, Philip N., Prince, Richard L. and Nicholson, Geoff C. (2012) Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation. PloS One, 7 8: .


Author Morrison, Nigel A.
Stephens, Alexandre A.
Osato, Motomi
Polly, Patsie
Tan, Timothy C.
Yamashita, Namiko
Doecke, James D.
Pasco, Julie
Fozzard, Nicolette
Jones, Graeme
Ralston, Stuart H.
Sambrook, Philip N.
Prince, Richard L.
Nicholson, Geoff C.
Title Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-08-13
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pone.0042617
Volume 7
Issue 8
Total pages 11
Place of publication San Francisco, United States
Publisher Public Library of Science
Collection year 2013
Language eng
Abstract RUNX2 is an essential transcription factor required for skeletal development and cartilage formation. Haploinsufficiency of RUNX2 leads to cleidocranial displaysia (CCD) a skeletal disorder characterised by gross dysgenesis of bones particularly those derived from intramembranous bone formation. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Since none of the known mutations causing CCD characterised to date map in the glutamine repeat region, we hypothesised that Q-repeat mutations may be related to a more subtle bone phenotype. We screened subjects derived from four normal populations for Q-repeat variants. A total of 22 subjects were identified who were heterozygous for a wild type allele and a Q-repeat variant allele: (15Q, 16Q, 18Q and 30Q). Although not every subject had data for all measures, Q-repeat variants had a significant deficit in BMD with an average decrease of 0.7SD measured over 12 BMD-related parameters (p = 0.005). Femoral neck BMD was measured in all subjects (20.6SD, p = 0.0007). The transactivation function of RUNX2 was determined for 16Q and 30Q alleles using a reporter gene assay. 16Q and 30Q alleles displayed significantly lower transactivation function compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency of about 0.4%. These mutations significantly alter BMD and display impaired transactivation function, introducing a new class of functionally relevant RUNX2 mutants.
Keyword Bone mineral density
Cleidocranial dysplasia
Osteoblast differentiation
Postmenopausal women
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article #42617

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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